Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive degeneration of corticospinal and spinal motor neurons. Most cases are sporadic (sALS), but about 5-10% of patients have an inherited familial form of the disease. About one-fifth of these is linked to mutations in the gene coding for the SOD1 protein. Transgenic animals carrying single-amino acid mutations of human SOD1 develop progressive motor neuron disease that recapitulates in many aspects the human pathology. The cascade of events ultimately responsible for motor neuron degeneration, however, remains elusive. Recent observations suggest that a complex pathological interplay subsists between motor neurons and the neighboring glial cells.
In the adult nervous system, the major glial cell type is represented by the astrocytes. These cells fulfill several homeostatic functions that collectively contribute to maintain the optimal microenvironment for neuronal function and survival. In addition, astroglial cells can sense neuronal activity by means of a wide array of neurotransmitter receptors located in their plasma membrane and, in turn, they can respond to neurons by Ca2+-dependent release of gliotransmitters. The multiplicity and complexity of these activities clearly indicates that the correct performance of the astrocytes is crucial for the physiological functioning of the nervous system, and its derangement may affect neuronal activity and contribute to neurodegeneration.
A crucial indication that astrocyte alterations are implicated in ALS progression in vivo came from the observations that reducing mutant SOD1 expression within astrocytes significantly affected the progression of the disease in transgenic mice. In keeping, ALS-linked mutant SOD1-expressing astroglial cells in culture were reported to secrete factors that are toxic to motor neurons. Furthermore, in both ALS patients and transgenic animals, there is evidence for biochemical and functional alterations of the astrocytes. Within this framework, a degenerative process of the astrocytes, positioned in the microenvironment of motor neurons, was reported in the spinal cord of transgenic mice over-expressing the mutant human SOD1G93A (hSOD1G93A) protein. This phenomenon occurs prior to symptom onset and is mediated by the excitatory amino acid glutamate via the activation of its inositol 1,4,5 triphosphate (IP3)-producing metabotropic receptor type-5 (mGluR5). Consistent evidence indicates that the physiological production of IP3, under the stimulation of cell-surface receptors, such as mGluR5, normally triggers the release of Ca2+ from the endoplasmic reticulum (ER) by opening the IP3 receptor (IP3R) channels.
Such Ca2+ plays a role in modulating a variety of cellular responses that are fundamental for cell function and survival. However, Ca2+ released under non-physiological conditions can activate different pathways of cell death.
It follows that the identification of pharmacological agents that modulate the release of Ca2+ from the ER may be relevant to prevent astroglial cell death in ALS, and thus contribute to overcome the symptoms and manifestations of the disease.